Combinatorial signaling in zebrafish development

斑马鱼发育中的组合信号

• 批准号: 6721219
• 负责人: David Kimelman
• 金额: $ 79.28万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2006-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6721219
• 关键词: biological signal transduction; developmental genetics; transcription factor; vertebrate embryology

DESCRIPTION (provided by applicant): Intercellular signaling plays a critical role in patterning embryonic development and in the regulation of cell proliferation and survival in embryos and adults. By temporally and spatially combining signals from different signaling pathways, organisms gain the ability to produce complex cellular decisions through the activation of target genes that respond to multiple signaling factors. How these combinatorial signals are used at the molecular and cellular level is for the most part not well understood. The central question of this proposal is: how do Bmps and Wnts work together to establish genetic hierarchies leading to the formation of the posterior mesoderm and neural crest? To examine this, three avenues will be pursued using zebrafish as a model system. (1) Transgenic zebrafish expressing Bmp and Wnt/B-catenin activators and inhibitors under heat shock control will be used to determine when and how these signals are used to regulate the formation of the posterior mesoderm and neural crest throughout development. (2) The promoters of several key target genes responding to Bmp and Wnt/B-catenin signals will be analyzed in order to understand how these signaling pathways are ultimately integrated at the transcriptional level. (3) Microarray and subtractive screens will be used to identify genes that are regulated by both Bmp and Wnt/B-catenin signals using zebrafish mutants that have defects in the Bmp and Wnt signaling pathways. A critically chosen subset of these genes, which are expressed in the posterior mesoderm and neural crest, will be selected for further study using a combination of the transgenic fish expressing inducible Bmp and Wnt activators and inhibitors, overexpression studies and morpholino antisense oligonucleotides. Finally, this analysis will provide a molecular framework for understanding how combinatorial Bmp and Wnt signals lead to the formation of specific tissues within the embryo. Since both Bmp and Wnt signaling are involved in disease processes in humans, and since these signaling pathways are highly conserved, this research will have direct relevance to understanding mechanisms of human disease.

描述（由申请人提供）：细胞间信号传导发挥着重要作用 在胚胎发育模式和细胞调节中发挥关键作用 胚胎和成体的增殖和存活。通过时间和空间 结合来自不同信号通路的信号，生物体获得了这种能力 通过激活靶基因产生复杂的细胞决策 对多种信号因素作出反应。这些组合信号是如何产生的 在分子和细胞水平上使用大部分都不好 明白了。该提案的核心问题是：Bmps 和 Wnts 如何工作 共同建立遗传等级，从而形成 后中胚层和神经嵴？为了检验这一点，将通过三个途径 使用斑马鱼作为模型系统进行研究。 (1) 转基因斑马鱼表达 Bmp 和 Wnt/B-连环蛋白激活剂和抑制剂在热休克控制下将 用于确定何时以及如何使用这些信号来调节 在整个发育过程中后中胚层和神经嵴的形成。 (2)响应Bmp和的几个关键靶基因的启动子 将分析 Wnt/B-连环蛋白信号，以了解这些信号如何 信号通路最终在转录水平上整合。 (3) 微阵列和消减筛选将用于鉴定基因 使用斑马鱼突变体受 Bmp 和 Wnt/B-catenin 信号调节 Bmp 和 Wnt 信号通路存在缺陷。严格选择的子集 这些基因在后中胚层和神经嵴中表达， 将选择使用转基因鱼的组合进行进一步研究 表达诱导型 Bmp 和 Wnt 激活剂和抑制剂、过度表达 研究和吗啉代反义寡核苷酸。最后，本次分析将 提供一个分子框架来理解 Bmp 和 Wnt 的组合 信号导致胚胎内特定组织的形成。既然两者 Bmp 和 Wnt 信号传导参与人类疾病过程，并且自那时起 这些信号通路是高度保守的，这项研究将有直接的 与理解人类疾病机制的相关性。